Skin Care and Treatments of Melbourne Dermatology - Telomerase

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Telomerase

Telomerase

Telomerase is an an enzyme that adds nucleotides to telomeres, especially in cancer cells.

Wednesday, 3 September 2008

Decipering of Telomerase Structure Opens Door To New Cancer, Aging Treatments

Researchers at The Wistar Institute have deciphered the structure of the active region of telomerase, an enzyme that plays a major role in the development of nearly all human cancers. The landmark achievement opens the door to the creation of new, broadly effective cancer drugs, as well as anti-aging therapies.

Researchers have attempted for more than a decade to find drugs that shut down telomerase - widely considered the No. 1 target for the development of new cancer treatments - but have been hampered in large part by a lack of knowledge of the enzyme's structure.

The findings, published online August 31 in Nature, should help researchers in their efforts to design effective telomerase inhibitors, says Emmanuel Skordalakes, Ph.D., assistant professor in Wistar's Gene Expression and Regulation Program, who led the study.

"Telomerase is an ideal target for chemotherapy because it is active in almost all human tumors, but inactive in most normal cells," Skordalakes says. "That means a drug that deactivates telomerase would likely work against all cancers, with few side effects."

The study elucidates the active region of telomerase and provides the first full-length view of the telomerase molecule's critical protein component. It reveals surprising details, at the atomic level, of the enzyme's configuration and how it works to replicate the ends of chromosomes - a process critical to both tumor development and the aging process.

Achieving immortality

In humans, telomerase adds multiple repeats of a short DNA sequence to the ends of chromosomes, known as telomeres, thus preventing damage and the loss of genetic information during cell division.

When telomerase is dormant, telomeres shorten each time a cell divides, leading eventually to genetic instability and cell death. By preserving chromosomes' integrity, telomerase allows cells to continue living and dividing. The enzyme is active in cells that multiply frequently, such as embryonic stem cells, but is switched off almost entirely in normal adult cells to prevent the dangers of runaway cell proliferation.

Cancer cells, however, often regain the ability to activate telomerase, which has been implicated in 90 percent of human tumors. The enzyme permits cells to replicate indefinitely and achieve the cellular "immortality" that is the hallmark of cancer. Deactivating telomerase would stop tumor growth.

In addition to its role in cancer, telomerase holds significant implications for the development of therapies to combat aging and other age-related diseases. Finding ways to activate telomerase under controlled conditions and allow some cells to begin dividing again could result in healthier, younger-looking tissue that lives longer.

An elusive enzyme

Telomerase is a complex structure made up of multiple protein domains and a stretch of RNA, which contains the template the enzyme uses to synthesize telomeres.

Last year, Skordalakes and his team solved the structure of a key segment of the molecule - the so-called TRBD domain, where RNA binding occurs. However, the complexity of telomerase has proved a roadblock to determining the enzyme's overall architecture - a goal pursued by researchers worldwide for more than 15 years.

To perform the necessary studies, scientists first must gather large quantities of the enzyme in a specific conformation. Because the complex structure of telomerase most likely allows it to change configuration, that process has been challenging, Skordalakes says.

To find sufficient quantities of the enzyme for the study, Skordalakes and his team looked beyond commonly relied-on sources such as humans and yeast. By screening a wide variety of organisms, including protozoa and insects, they discovered that a gene from the red flour beetle could produce telomerase in copious amounts, and a stable form.

"That was really the breakthrough," Skordalakes says. "Once we found that the gene from this organism expressed the protein in the quantities we needed, we were able to move quickly."

The researchers used X-ray crystallography, a technique that analyzes the diffraction patterns of X-rays beamed at crystals of a molecule, to determine the three-dimensional structure of the enzyme's active region - the catalytic component called telomerase reverse transcriptase protein, or TERT.

The study revealed surprising features, including the fact that the molecule's three domains are organized into a doughnut shape, an unexpected configuration. Knowledge of the structure allowed the researchers to create a model of the enzyme's function.

"It's extremely exciting," Skordalakes says. "For the first time, we can see how telomerase assembles at the end of chromosomes to initiate telomere replication."

Looking ahead

Skordalakes plans to further study TERT and search for new telomerase inhibitors that could become cancer therapies. He also will look at modifying existing drugs. Previous attempts to target telomerase have fallen flat, but knowledge of the enzyme's structure will help researchers to determine the limitations of existing agents and make them more effective.

Skordalakes began his studies of telomerase when he joined The Wistar Institute in 2006 and established his first laboratory. "I've always been interested in understanding, on a molecular level, the function of protein nucleic acid assemblies and using that information in the treatment of human disease," he says. "Telomerase, because of its important role in cancer and aging, was an obvious target for me."

He says though the process was frustrating at times, his team was determined to solve the structure. "It required a lot of perseverance and effort, but we really wanted to do this," he says.

----------------------------

Article adapted by Medical News Today from original press release.

----------------------------

Wistar's Andrew J. Gillis and Anthony P. Schuller assisted with the study.

The research was supported in part by the Commonwealth Universal Research Enhancement Program of the Pennsylvania Department of Health and the Ellison Medical Foundation.

The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the country, Wistar has long held the prestigious Cancer Center designation from the National Cancer Institute. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. The Wistar Institute: Today's Discoveries -Tomorrow's Cures. On the Web at The Wistar Institute.

Wednesday, 7 November 2007

Telomere Maintenance

By making mice grow furrier coats, researchers have discovered that an enzyme known to serve as a last-ditch defense against cancer also activates adult stem cells, which the body uses to repair its tissues.

The insight could lead to new treatments for certain diseases, possibly even promoting hair growth in animals other than mice.

The research, reported by Steven E. Artandi and colleagues at Stanford University in Nature Today, shows that adult stem cells can be activated by an enzyme called telomerase.

The finding is surprising because telomerase is well known in a quite different context, protecting against tumors by limiting the number of times a cell can divide.

The new findings put the enzyme astride two major biological pathways, one that promotes the growth of new cells for maintaining tissues and the other that prevents the excessive growth that leads to tumors.

The finding is "very interesting and very tantalizing," said Carol Greider, a telomerase expert at the Johns Hopkins University, who was not involved in the research.

Dr. Artandi chose to study the effects of telomerase on mouse fur not to develop a Rogaine for rodents, but because mice have an easily accessible stem cell system built into their skin. Each hair follicle has attached to it a small bulb full of stem cells. When the stem cells are activated, the follicle grows a new hair shaft.

Dr. Artandi's team genetically engineered a strain of mice in which the telomerase gene could be turned on with a drug. When the mice were given this drug, the stem cells in their hair follicles proliferated, and the mice grew extra furry coats.

The usual role of telomerase is to maintain the telomeres, special lengths of DNA that cap each end of the chromosomes. But it performs this service only for egg and sperm cells and to some extent for stem cells.

Shortening Telomere

The telomerase gene is switched off almost entirely in normal cells. So each time a normal cell divides, its telomeres become shorter, and after they dwindle to a certain length, the cell is forced into senescence and cannot divide again.

For several years, there have been hints that the telomerase protein performs some role other than just maintaining telomeres. Dr. Artandi said he had decided to look for that role in stem cells, because the gene that makes the enzyme is active in these cells.

To avoid confusion with the telomere-lengthening role of telomerase, he engineered the mice to lack the additional biochemical machinery needed to maintain telomeres. Thus when the mice were fed the telomerase-activating drug, the telomerase must have activated the stem cells in some way that did not involve their telomeres.

Dr. Artandi said he did not yet know how telomerase activated stem cells. But when this new pathway is understood, it may suggest ways of tackling diseases in which the right cells fail to proliferate like pancreatic islet cells in diabetes.

Normal male mice do not go bald as they age, but the research could still be significant for human beings. Anthony Oro, a dermatologist and co-author of the report, said the great challenge in male-pattern baldness was how to restart the arrested follicles.

The finding about telomerase in mice "doesn't prove that this is the master regulator of all hair follicle cycling," Dr. Oro said, but it helped define the players.

Telomerase experts not involved in this study are enthusiastic about the finding, which opens out an unexpected line of inquiry about their favorite gene. "I think it is an extremely important observation," said Ron DePinho of the Harvard Medical School.

Elizabeth Blackburn of the University of California, San Francisco, said that "biologically it's intriguing" that telomerase should have two such different roles. But, Dr. Blackburn added, it is too early to know whether this is just one of nature's frequent economies in using the same protein to do two things.


Furrier Mice Yield Stem-Cell Discovery, Nicholas Wade, August 18, 2005.

Emphasis and annotations added.

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